Download Abnormal Uterine Bleeding in Reproductive

Case-based review
Abnormal Uterine Bleeding in ReproductiveAged Women
Kirsten Rindfleisch, MD, Julianne Falleroni, DO, MPH, and Sarina Schrager, MD, MS
Abstract
• Objective: To describe the contributing etiologies,
common presentations, diagnosis, evaluation, and
management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3
cases.
• Results: AUB is one of the most common reasons
that reproductive-aged women seek health care. The
causes are varied, depending in large part on the
age and life stage of the woman. Diagnosis requires
a systematic approach that is driven by a thorough
health history and review of presenting symptoms. Determining whether the bleeding is ovulatory or
anovulatory is a central part of the evaluation. A
methodical history, physical examination, and laboratory evaluation may enable the physician to rule out
causes such as pregnancy and pregnancy-related
disorders, medications, iatrogenic causes, systemic
conditions, and obvious genital tract pathology. • Conclusion: Clinicians must be knowledgeable about
AUB and partner with women to develop appropriate,
individualized treatment plans.
A
bnormal vaginal bleeding is a common complaint in primary care. The prevalence of some
type of abnormal bleeding is up to 30% among
women of reproductive age [1]. Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2]. A retrospective analysis of medical
expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women
with abnormal bleeding were more likely to be younger,
Caucasian, and obese and had poorer physical and mental
health quality of life scores [3].
The estimated direct and indirect costs of abnormal
bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include
time off from work and cost of products to protect clothwww.jcomjournal.com
ing from bleeding (eg, tampons and pads). Abnormal
bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25%
of all gynecologic surgeries [5].
History Taking
Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or
abnormal. Regularity of menstrual bleeding is clarified by
asking about the frequency of the menses and their duration. Other important questions include age at menarche,
presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual
symptoms whereas an anovulatory cycle will be random in
its symptomatology. Women’s estimates of the amount of
menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is
considered menorrhagia. However, women and their health
care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of
women who presented with menorrhagia actually had more
than 80 cc of blood loss [6]. There is movement toward
use of more patient-centered measures to diagnose menorrhagia, such as bleeding interfering with a woman’s daily
activities, needing to wake up at night to change tampons or
pads, or inability to exercise during menses. Anemia in the
setting of menorrhagia by history is a less subjective way to
diagnose menorrhagia.
Nomenclature and Differential Diagnosis
In 2011, the International Federation of Gynecology
and Obstetrics (FIGO) published a new classification
system for abnormal uterine bleeding. The American
College of Obstetrician-Gynecologists has also endorsed
From the University of Wisconsin School of Medicine and
Public Health, Madison, WI.
Vol. 22, No. 2 February 2015 JCOM 83
Abnormal uterine bleeding
Table 1. Common Causes of Abnormal Vaginal Bleeding
PALM (structural causes)
Polyp
Endometrial polyps
Cervical polyps
Adenomyosis
Leiomyoma
Submucosal fibroids
Other leiomyomas
Malignancy and hyperplasia
Endometrial hyperplasia
(eg, abnormal uterine bleeding caused by ovulatory disorders is referred to as AUB-O). The term dysfunctional
uterine bleeding, used in the past to describe abnormal
bleeding, is being replaced by these terms.
Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any
type of abnormal bleeding in any woman of reproductive
age (ie, after menarche and before menopause). Many
systemic illnesses and medications can affect menstrual
bleeding and should be included in a broad differential
diagnosis of a presenting woman.
Hyperplasia with atypia
CASE 1—HEAVY MENSTRUAL BLEEDING
Endometrial carcinoma
Initial Presentation
COEIN (non-structural causes)
Coagulopathy
Liver failure
Anticoagulant use
Inherited bleeding disorders (von Villebrand’s disease most
common)
Ovulatory dysfunction
A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods
over the last 6 to 8 months. She experienced menarche
at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any intermenstrual bleeding.
Physiologic (adolescence, perimenopause, lactation)
Polycystic ovary syndrome
Female athlete triad
• What additional history should be obtained?
Hypothalamic dysfunction (eg, eating disorder, stress)
Thyroid disease
Hyperprolactinemia
Pituitary disorder
Primary ovarian insufficiency
Iatrogenic (eg, from radiation or chemotherapy)
Endometrial
Hormonal imbalance
Endometrial atrophy
Iatrogenic
Endogenous hormones (contraception, HRT, IUD)
Anticoagulant use
Not yet classified
Vaginitis
Cervicitis
this new classification system [7]. The system divides
etiology of abnormal uterine bleeding into structural and
non-structural causes and follows the acronym PALMCOEIN (Table 1). New nomenclature uses the acronym
AUB (abnormal uterine bleeding) with the initial from
the classification system as a description of the disorder
84 JCOM February 2015 Vol. 22, No. 2
Heavy menstrual bleeding refers to abnormally heavy
bleeding that occurs in an ovulatory, cyclical pattern.
Women with anovulatory cycles can also have heavy
bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.
The initial evaluation of a woman presenting with
heavy menstrual bleeding includes a detailed history
and physical examination. The first goal of the history is to establish the severity of bleeding, including
any symptoms of hemodynamically significant anemia
such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is
ovulatory or anovulatory. Ovulatory heavy menstrual
bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps,
and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be
due to systemic illness (including thyroid disease, renal
disease, and liver disease) or endometrial hyperplasia or
carcinoma.
Once an ovulatory pattern is confirmed, a history of
dysmenorrhea, pelvic pain, lower urinary tract symptoms,
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constipation, dyspareunia, or infertility should be elicited. These symptoms may be reported by patients with
leiomyomas or endometriosis (Table 2). In contrast,
most women with endometrial polyps do not have any
other symptoms in addition to heavy menstrual bleeding.
Cervical polyps may also cause postcoital bleeding in addition to heavy menstrual bleeding.
Further history taking should seek to identify any
symptoms suggestive of thyroid, kidney, or liver disease,
as well as any medications or supplements known to
confer an increased risk of bleeding such as warfarin or
other anticoagulants. A key component of the history is
the search for indications of a coagulopathy, including a
personal or family history of postpartum hemorrhage or
significant postoperative bleeding, or a history of recurrent naso- or oropharyngeal bleeding or unexplained
bruising. Finally, the clinician should elicit risk factors
for endometrial carcinoma, including a prior history of
oligomenorrhea (resulting in unopposed estrogen exposure), obesity, or diabetes (Table 3).
Table 2. Causes of Ovulatory Heavy Menstrual Bleeding
Leiomyoma
Endometriosis
AUB-E (local endometrial factors)
Iatrogenic (medications, copper IUD)
Endometrial hyperplasia/carcinoma
Adenomyosis
Hypothyroidism
Systemic illness (chronic kidney disease, chronic liver disease)
Table 3. Risk Factors for Endometrial Cancer Known Risk Factors
Unopposed estrogen therapy
Tamoxifen
Chronic anovulation
Obesity
Diabetes mellitus
Family history of endometrial cancer
Lynch syndrome
Early menarche
• What are key elements of the physical examination?
Nulliparity
Possible Risk Factors
Estrogen-progesterone hormone replacement
The physical examination should include visual inspection
and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower
abdominal tenderness or masses. Signs of anemia such
as pallor should also be noted. The gynecologic exam
should include visual inspection of the external genitalia,
a bimanual exam, and a speculum exam. Cervical and
endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged
mobile uterus with irregular contours is consistent with
leiomyomas [8]. Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the
vaginal canal, the uterosacral ligaments, or the adnexa.
Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9]. Adenomyosis may cause diffuse moderate uterine enlargement
with or without tenderness [10]. Endometrial carcinoma
may also cause uterine enlargement and/or immobility.
• What laboratory testing should be performed?
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Phytoestrogens
Late menopause
BRCA1 mutation
Laboratory testing should include a pregnancy test and
complete blood count (CBC). The CBC is important
to assess the severity of the bleeding, which may not be
apparent by history and physical examination alone. A
screening thyroid-stimulating hormone test is commonly
obtained, though only 7% of hypothyroid women report
heavy menstrual bleeding [11]. A prolactin level should be
obtained. Von Willebrand factor deficiency is an underdiagnosed cause of heavy menstrual bleeding, and further
testing is recommended if the history is suggestive, especially for women with a history of heavy bleeding since
menarche [12]. This testing should include prothrombin
time, partial thromboplastin time, von Willebrand factor
antigen, von Willebrand factor activity (ristocetin cofactor activity), and factor VIII activity. Creatinine and liver
function testing should be obtained if indicated based on
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Abnormal uterine bleeding
Table 4. Laboratory Evaluation of Women with Heavy
Menstrual Bleeding Indicated for All Patients
Pregnancy test (urine HCG)
Complete blood count (CBC)
Thyroid stimulating hormone (TSH)
endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly
delineated on sonohysterogram. Women who have a
negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further
evaluation.
Prolactin
Case Continued
Indicated Based on History
The patient reports that her periods are regular,
with a cycle length of 30 to 31 days. She usually
notes some bloating and breast tenderness in the days
leading up to onset of menses. She experiences lower
abdominal cramping during days 1–3 of her period. This
has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history
is significant for 3 uncomplicated vaginal deliveries and
1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of
significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual
and speculum exam. Laboratory evaluation demonstrates
a low-normal hemoglobin, hematocrit, and MCV. The
TSH is normal and a urine pregnancy test is negative.
She had a normal pap smear and HPV assay 2 years ago.
Prothrombin time (PT)
Partial thromboplastin time (PTT)
Von Willebrand factor antigen
Von Willebrand factor activity (ristocetin cofactor activity)
Factor VIII activity
Serum creatinine
Serum transaminases, alkaline phosphatase, srum bilirubin
the history and physical exam (Table 4).
• What additional testing would be useful in narrowing the differential diagnosis?
If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of
symptom management or proceed with further testing (imaging and/or tissue sampling) is based on
risk of endometrial cancer, severity of symptoms,
and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult,
which may lower the threshold for obtaining a pelvic
ultrasound.
Women with risk factors for endometrial cancer should
undergo office-based endometrial biopsy as the first
step in evaluation of heavy menstrual bleeding [7]. Risk
factors include older age (45 years and older), obesity
(BMI > 30), diabetes mellitus, nulliparity, and history
of chronic anovulation (eg, polycystic ovary syndrome).
Pelvic ultrasound is the first step in the evaluation of
women with an abnormal physical exam suggesting a
structural lesion [7]. If the physical exam is abnormal and
the pelvic ultrasound is nondiagnostic, a hysteroscopy or
saline-infusion sonohysterogram should be performed,
as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13]. Most
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• What is the most likely diagnosis?
• What treatment is recommended?
High quality evidence to support pharmacologic treatment for heavy menstrual bleeding due to fibroids is
limited. Data supporting the efficacy of oral NSAIDs,
estrogen-progestin oral contraceptive pills, and oral
progestins is inconsistent. However, due to the relative
low expense and low risk of side effects, a trial of one of
these medications is reasonable as a first line treatment.
In some studies, the levonorgestrel-releasing intrauterine
system has been shown to decrease menstrual blood loss
though not to reduce fibroid size [14,15]. Treatment options for heavy menstrual bleeding are shown in Table 5.
Oral tranexamic acid is an anti-fibrinolytic that was
recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used
for many years to prevent bleeding during surgery and
to treat bleeding disorders. It has been used for over 30
years to treat menorrhagia in Europe. It has a different
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mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for
women who cannot tolerate other medication options
[16,17]. Tranexamic acid is contraindicated in women
with an elevated risk of thromboembolic disease.
For women who have insufficient response to medical
management or for women who present with more severe
symptoms, anemia, or prominent bulk-related symptoms
due to fibroids, gynecologic referral should be made for
consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid
tumors depends upon the type of fibroid (eg submucosal,
intramural, subserosal), the number of fibroids, desire for
future childbearing, risk for surgical complications, and
patient preference. Effective options include myomectomy,
uterine artery embolization, endometrial ablation, and
hysterectomy [18].
By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding
when it occurs in the setting of endometriosis. Estrogenprogestin oral contraceptive pills, oral progestins, and
depot medroxyprogesterone have all been demonstrated
to be effective in decreasing pain [19,20]. The levonorgestrel-releasing intrauterine system is also effective in
decreasing pain due to endometriosis [21].
Women who do not respond to first-line therapy
should be referred to a gynecologist for consideration
of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH
agonists, and surgical approaches such as laparoscopic
ablation and/or excision of endometriosis implants [22].
A similar range of treatment options appears to be
effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral
NSAIDs, oral tranexamic acid, estrogen-progestin oral
contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24]. Women with an inadequate
response to first-line treatment should be referred to a
gynecologist for consideration definitive treatment with
hysterectomy versus uterine artery embolization or a trial
of a GnRH agonist [24].
For some women with heavy menstrual bleeding,
no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of
local endometrial hemostasis leading to increased blood
loss during otherwise normal menstrual cycles [25]. The
levonorgestrel-releasing intrauterine system may be the most
effective medical therapy for heavy menstrual bleeding in the
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Table 5. Treatment Options for Heavy Menstrual
Bleeding
Cause
Treatment Options to Consider
Leiomyoma
NSAIDs, tranexamic acid
Estrogen-progesterone OCPs
Oral progesterone
Levonorgestrel IUS
Endometrial ablation
Uterine artery embolization
Myomectomy
Hysterectomy
Endometriosis
NSAIDs, tranexamic acid
Estrogen-progesterone OCPs
Oral progesterone
Depot medroxyprogesterone
Danazol
GnRH agonists
Laparoscopic ablation
Cervical polyps
Office-based removal
Hysteroscopic removal
Endometrial polyps
Hysteroscopic removal
AUB-E
NSAIDs, tranexamic acid
Estrogen-progesterone OCPs
Oral progesterone
Levonorgestrel IUS
Endometrial ablation
Adenomyosis
NSAIDs, tranexamic acid
Estrogen-progesterone OCPs
Levonorgestrel IUS
GnRH agonist
Uterine artery embolization
Hysterectomy
Endometrial hyperplasia
Progestin therapy
Hysterectomy
Endometrial carcinoma
Options dependent upon staging
absence of a specific target lesion [26]. For women wishing
to avoid hormonal treatment, scheduled oral NSAIDs or
oral tranexamic acid are inexpensive and effective options
for reducing blood loss [27–29]. Other medical treatment
options include estrogen-progestin contraceptive pills, cyclic
oral progestin, and depot medroxy-progesterone.
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Abnormal uterine bleeding
Table 6. Causes of Anovulatory Bleeding
Physiologic
Adolescence or perimenarche
Perimenopause or menopausal transition
Pregnancy
Lactation
Pathologic
Hyperandrogenic state
Polycystic ovary syndrome
CASE 2—ANOVULATION
Initial Presentation
A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and
her husband are attempting pregnancy and she seems
disappointed that the pregnancy test is negative. She is
having trouble tracking her periods. Her cycles range
from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are
heavy with soaking tampons/pads.
Congenital adrenal hyperplasia
Androgen producing tumors
Hypothalamic dysfunction
Anorexia
• What are diagnostic considerations in evaluating this bleeding pattern?
Other eating disorders
Female athlete triad
Hyperprolactinemia
Thyroid disease
Uncontrolled diabetes
Primary pituitary disease
Premature ovarian failure
Iatrogenic
Radiation
Chemotherapy
Medication effects
Antiepileptics
Antipsychotics
Adapted from references 29 and 32.
Menstrual history can help differentiate between of
ovulatory and anovulatory abnormal bleeding. Typically,
anovulatory bleeding is marked by irregular or infrequent
periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common
ovulation symptoms (thin watery cervical mucus) or premenstrual symptoms (breast tenderness) [31].
The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine
bleeding due to ovulatory dysfunction” or “anovulatory
abnormal uterine bleeding” [7,31]. In general, if women
are having menses at regular cycles their bleeding is likely
to be ovulatory.
Differential Diagnosis
For patients who experience treatment failure with
pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have
been shown to be effective and associated with high rates
of patient satisfaction [30].
Follow-up
The patient reports that she would like to avoid
invasive testing if possible. Given her relatively
low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles
she reports that her heavy bleeding has not been wellcontrolled. A pelvic ultrasound demonstrates an anterior
submucosal fibroid measuring 2.4 cm and a posterior
intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to
report a significant decrease in her bleeding.
88 JCOM February 2015 Vol. 22, No. 2
Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3
years. Women entering perimenopausal transition may
also experience intermittent anovulation and subsequent
abnormal uterine bleeding. Other physiologic examples
include lactation and pregnancy [31].
Pathologic causes of anovulatory uterine bleeding
include hypothalamic dysfunction (secondary to eating
disorders, low BMI), primary pituitary disease, thyroid
disease, diabetes, and hyperprolactinemia (not related to
lactation). Hyperandrogenic anovulation is another subset of endocrine conditions and includes polycystic ovary
syndrome (PCOS). Medications such as antiepileptics,
typical and some atypical antipsychotics can contribute
by causing weight gain, hyperandrogenism, and elevated
prolactin [31,32] (Table 6).
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Physical Examination
Case Continued
A thorough history will help to narrow the differential
diagnosis. The physical exam can evaluate for other
findings that indicate endocrine dysfunction such as
low body weight, hirsutism, balding, acne, high blood
pressure, obesity (especially centripetal fat distribution).
Acanthosis nigricans is a sign of insulin resistance which
is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a
bimanual exam can reveal adnexal enlargement indicative
of cystic ovaries. Of note, clitoromegally is not common
in PCOS. This finding would increase the likelihood of
other causes of hyperandrogenism [32].
The patient reports menarche at age 12. Her
periods were irregular for the first 1–2 years
but became more regular after that. She has been taking combination oral contraceptives since the age of 20
to prevent pregnancy. She stopped this 1 year ago and
she and her husband began actively trying to conceive
6 months ago. Her family history is notable for diabetes
and hypertension in her father. Her mother had heavy
periods leading up to menopause and had a hysterectomy
with no malignancy at the age of 47. She has a BMI of
33; blood pressure is mildly elevated at 134/84 mm Hg.
She has oily skin and acne along her chin and neck. She
has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of
35 inches. The remainder of her exam is normal.
• What is the pathophysiologic basis for this
patient’s bleeding pattern?
Pathophysiology of Anovulatory Bleeding
Anovulatory bleeding presumes that there is a normal
anatomic and genetic makeup. For example, a woman
without ovaries will be, by definition, anovulatory. Using
current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is
therefore primarily an endocrine disorder [31,33].
At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium.
After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes
the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of
endometrial lining. The endometrium becomes unstable,
undifferentiated, and sheds unpredictably. The blood
vessels become larger, more tortuous and have increased
fragility. The result is light or heavy menstrual bleeding,
decreased frequency of periods but overall unpredictable
menstrual bleeding [33].
Effects of Chronic Anovulation
Irregular cycles can be more than a mere inconvenience.
Women who have anovulatory cycles associated with
heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility
and its treatment are common sequelae. Finally, over
time, unopposed estrogen in anovulation increases the
risk of endometrial hyperplasia, or cancer [7,34].
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• What is the likely diagnosis?
Based on her history and physical, this patient has a high
likelihood of having PCOS. PCOS is a common cause
of anovulation [32,35]. The cause is considered multifactorial. PCOS is a hyperandrogen state that includes
anovulation and increased ovarian androgen production.
Several sets of diagnostic criteria have been proposed,
all including some combination of oligo- or anovulation, clinical or biochemical signs of excess androgen,
and ultrasound evidence of polycystic ovaries. Currently
it is diagnosed when at least 2 criteria are met. These
include olio- or anovulation, biochemical signs of excess
androgen, and ultrasound evidence of polycystic ovaries
[32,35] (Table 7). Secondary causes of hyperandrogenism such as androgen-producing neoplasm, hyperprolactinemia and adult onset congenital adrenal hyperplasia
should be ruled out but these are less likely than PCOS
when classic symptoms and signs are found.
Women with PCOS are at increased risk for metabolic
syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and
infertility. Women with PCOS who become pregnant
have increased risk of pregnancy complications such as
hypertensive disorders and gestational diabetes.
• What tests are indicated in this patient?
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Abnormal uterine bleeding
Table 7. Recommended Diagnostic Criteria for Polycystic Ovary Syndrome
Signs and Symptoms
NIH Criteria 1990
Rotterdam Criteria
(2003) – 2 Required
Androgen Excess Society
(2006) – 2 Required
Hyperandrogenism
Required
Not required
Required
Oligomenorrhea
Required
Not required
Not required
Polycystic ovaries by ultrasound
Not applicable
Not required
Not required
Symptoms: hirsutism, acne acanthosis
nigricans
Biochemical markers
12 follicles measurine 2–9 mm
AND/OR
Ovarian volume greater than 10 mL
Adapted from references 32 and 33.
Appropriate laboratory testing is often determined based
on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years
after menarche is common and testing for pregnancy,
infection, and anemia are often sufficient. Menorrhagia
in adolescents warrants testing for bleeding disorders
as well [7]. Within 3 years of menarche, menstrual
cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes
and warrant additional evaluation. Pregnancy testing,
thyroid stimulation hormone and prolactin levels are
recommended first line evaluation [7,32,34]. If PCOS is
suspected an ultrasound can be performed but as noted
above, polycystic ovaries are not required to make the
diagnosis after adolescence.
Additional testing includes testosterone levels to look
for androgen secreting tumors. Late onset congenital
adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi
Jewish descent and those with a family history [34].
Morning hydroxyprogesterone can be performed to
evaluate for this. If women exhibit abrupt change in
menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can
detect Cushing’s syndrome [34].
In patients with PCOS, additional testing to evaluate
for medical comorbidities is recommended. This includes
screening for diabetes, dyslipidemia, and liver dysfunction.
The decision to perform endometrial evaluation depends on age, symptoms and other risk factors for endometrial hyperplasia or cancer. In women over 40, the
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risk is increased and chronic anovulation becomes more
concerning. Even though endometrial cancer is rare in
women age 19 to 39, those with increased risk for endometrial cancer such as nulliparity, hypertension, obesity,
family history endometrial sampling could be considered,
especially for patients who do not respond to initial treatment [7] (Table 8).
Case Continued
The patient’s prolactin and TSH are normal.
Tests for diabetes are normal. Her LDL is
elevated to 162, triglycerides are 200, and her HDL is
38. The physician informs her that she meets criteria
for PCOS and also that she has obesity and metabolic
syndrome.
• What factors should be considered when
making treatment recommendations for this
patient?
Treatment for anovulation is guided by the goals of
therapy. Since anovulation is an endocrine abnormality,
medical treatment is first line [31]. If secondary causes
are diagnosed, these should be treated first. Other goals
of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing
ovulation in women with desired fertility, and reducing
androgenic sequelae such as acne and hirsutism.
When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous
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Table 8. Proposed Laboratory Evaluation for Anovulatory Bleeding Based on Age
Menarche to Age 18
Physiologic Most Likely
Age 18 to 44
Anovulatory
Age 45 to Menopause
Anovulatory Plus Age
CBC—anemia if heavy bleeding
hCG
hCG
hCG—rule out pregnancy
TSH
TSH
GC/chlamydia—rule out infection/cervicitis
Prolactin
Prolactin
Endometrial sampling if obese, 2+ years of anovulation/abnormal bleeding or failure to respond to medical treatment
Endometrial sampling if risk factors for endometrial atypia
Endometrial sampling recommended
Nulliparity
Obesity
Hypertension
Chronic anovulation
Diabetes
Family history of colon cancer
Age > 40
Adapted from references 7, 32, 33, and 53.
hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring).
Medroxyprogesterone (medroxyprogesterone acetate
5–10 mg daily) taken 10 to 14 days per month is another
option. Standard consideration for medical eligibility in
prescribing these agents should be considered (see U.S.
medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer
contraception, while cyclic progesterone does not. Both
offer cyclic withdrawal bleeding. A Cochrane review
did not find any RCTs comparing one to the other and
therefore either are reasonable options [36]. The levonorgestrel IUD is effective at treating AUB as well [31].
Women may still experience intermittent vaginal bleeding
or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.
All of the above treatments provide the additional
benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection
the endometrial hyperplasia with chronic anovulatory
cycles and unopposed estrogen [31].
In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae
of the condition. Weight loss has been shown to reduce
circulating androgen levels and increase ovulation. It
has been shown to reduce glucose and lipid levels and
hirsutism. Pregnancy rates increase as well. Weight loss
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achieved through medications and gastric bypass has
similar effects. There is no special diet that has been
shown to be more effective than another [32]. As little as
a 5% weight reduction from baseline can improve PCOS
symptoms [34,35].
Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of
added benefit above lifestyle modifications [34]. Statin
therapy can be considered in women with hyperlipidemia
and PCOS [32].
For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception
counseling and lifestyle modifications are again first line
[32]. Ovulation induction interventions carry increased
risk of multiple gestation. For ovulation induction,
clomiphene citrate is first line therapy. Metformin is
commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation
compared to placebo [37]. However, RCTs do not support its use as first-line treatment of infertility treatment
in PCOS. Clomiphene is 3 times more effective than
metformin alone [32].
Medications can improve but often do not resolve
hirsutism in women with PCOS. Combined hormonal
contraceptives are commonly used off-label and no one
type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can
also improve lipid and other metabolic variables. They
Vol. 22, No. 2 February 2015 JCOM 91
Abnormal uterine bleeding
Table 9. Evaluation of a Woman Who Has Unscheduled
Bleeding on Hormonal Contraception
History to determine any new medications, herbs, change in
weight, adherence to method
Urine hCG to exclude pregnancy
for 3 cycles of pills (9 weeks), and then takes a 7-day
pill-free week when she gets a menstrual period. This
had been working fine until the last 6 months. She has
noticed breakthrough spotting up to 2 weeks at a time
during the 2nd and 3rd pack of pills.
Assessment of cervical cancer screening
Evaluation for sexually transmitted infections
Consideration of secondary causes of bleeding abnormalities
(TSH, prolactin)
• What is the approach to evaluation and treatment in this patient?
Assessment of hemodynamic status (hemoglobin/hematocrit)
Assessment of risk of bleeding disorder
are all teratogenic and therefore should not be used in
women who desire conception, and be used with effective
contraceptives. Spironolactone is an androgen receptor
antagonist. It takes months for effect. Some women will
have improved menstrual frequency with this medication
as well. Often adjunctive therapy such as eflornithine
facial cream or laser therapy or a combination is needed
to further treat hirsutism [32,35,38].
Follow-up
After discussion, the patient decides to adopt
therapeutic lifestyle changes. She desires to get
pregnant and does not opt for hormonal contraceptives
at this time. She sees a nutritionist and begins calorie
restriction and exercise. Three months later she has lost 20
pounds and feels “healthier.” Her lipid panel shows LDL
of 125 and HDL of 43. Her triglycerides are now 160. Her
blood pressure in the office is 118/78 mm Hg. She has
lost “inches” around her middle. She has had more regular
periods as well. She is still not pregnant so the physician
asks her to begin tracking ovulation with cervical mucus
evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that
she misses a period but is pleased to report a positive home
pregnancy test.
CASE 3—BREAKTHROUGH BLEEDING ON
COMBINED HORMONAL CONTRACEPTIVES
Initial Presentation
A 28-year-old G0P0 in a monogamous
relationship presents to her physician. She has
been on oral contraceptive pills for 8 years. For the last
3 years she has been taking the pills on an extended
cycle schedule. She normally takes an active pill daily
92 JCOM February 2015 Vol. 22, No. 2
Bleeding in Women on Combined Hormonal
Contraception
Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the
traditional 21/7 schedule of active pills/pill-free week.
The FDA has approved several packaged extended-cycle
contraceptives. Extended-cycle contraception decreases
overall number of bleeding days and improves many
menstrual-related symptoms [39]. Breakthrough bleeding is the most common side effect of extended cycle
contraception. It is classified as AUB-I (abnormal uterine
bleeding—iatrogenic). It is most common in the first
few months of use, and decreases as use continues. Up
to 86% of women will have unscheduled bleeding during
the first 3 months of use of extended cycle contraception,
but this bleedingdecreases as use continues [40].
There is no consensus as to the underlying mechanism
causing this abnormal bleeding. Most clinicians believe
that it is related to the balance of estrogen/progestin in
each combined hormonal contraceptive. Each woman
reacts differently to this combination, making it difficult
to predict who will have abnormal bleeding. In women
who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize
within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in
women who take combined oral contraceptive pills [41].
In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding,
evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for
cervical cancer screening). A pelvic examination may help
determine a possible secondary cause of bleeding, but is
not necessary.
Treatment of unscheduled bleeding in women on
extended-cycle contraception includes shortening the
www.jcomjournal.com
Case-based review
hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal
contraception may be too long. One study demonstrated
that a 7-day hormone-free interval was associated with a
lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42]. A systematic review
found that shortened hormone-free intervals decreased
the amount of unscheduled bleeding [39]. A small RCT
(65 women) of continuous contraceptive ring users found
that the group that removed the ring for 4 days during
an episode of unscheduled bleeding, and then reinserted
it had overall reduction in unscheduled bleeding [43].
Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no
evidence to support this recommendation, but it can be
helpful in some women.
Low-dose doxycycline (40 mg daily) for prevention
of unscheduled bleeding shows promise [44]. This lowdose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive
users [44]. However, an RCT found that traditional-dose
doxycline (100 mg BID) taken for 5 days at the onset
of a bleeding episode, did not decrease the amount or
length of unscheduled bleeding [40]. Neither estrogen
dose [45] nor progestin dose [45] affected bleeding patterns. There is some suggestion based on a small study
that women on pills with norethindrone may have less
unscheduled bleeding than those who are on pills with
levonorgestrel, but more research needs to be done
before clinicians change practice [46]. A Cochrane review
looked at one small study that suggested third-generation
progestins had more favorable bleeding profiles than
second-generation progestins [47].
Follow-up
The physician investigates for secondary causes
of the bleeding. The patient’s urine hCG, TSH,
and prolactin levels are all normal. No fibroids or polyps
are seen on ultrasound. The physician and patient discuss
treatment options, including a low-dose doxycycline pill
to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes,
but the patient does not want to take 2 pills every day.
After further discussion, the patient decides she would
like to change to the contraceptive ring with the plan
of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the
www.jcomjournal.com
patient states that her unscheduled bleeding has been
controlled.
Corresponding author: Sarina Schrager, MD, MS, Dept. of
Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI
53715, [email protected].
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